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Efficacy of tirzepatide, lanifibranor, and resmetirom in metabolic dysfunction-associated steatotic liver disease: a meta-analysis of high-quality randomized controlled trials.

Intern Emerg Med

Shuai Zhao, Fei Tian, Lan Yu +6 more

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent condition and a leading cause of chronic liver disease worldwide. Several pharmacological agents are currently used in its clinical management. This meta-analysis assesses the comparative efficacy and safety profiles of three novel therapeutic agents-tirzepatide (a dual GIP/GLP-1 receptor agonist), lanifibranor (a pan-PPAR agonist), and resmetirom (a thyroid hormone receptor-β agonist)-in patients with MASLD/MASH.We systematically searched PubMed, Scopus, Web of Science, the Cochrane Library, and Embase from inception to December 31, 2024. Eligible randomized controlled trials (RCTs) were those that enrolled adults with MASLD/MASH and compared tirzepatide, lanifibranor, or resmetirom with placebo. Non-randomized trials, animal studies, trials using only imaging or biomarkers for diagnosis, studies without a placebo arm, and those including subjects aged < 18 years were excluded. Methodological quality was assessed using the Cochrane Risk of Bias 2.0 tool. Data synthesis was performed using RevMan 5.3. The protocol was registered with PROSPERO (CRD 42025637054). Five placebo-controlled trials met the inclusion criteria: one for tirzepatide (NCT04166773), one for lanifibranor (NCT04849728), and three for resmetirom (NCT03900429, NCT04197479, NCT04951219). The analysis included 2497 individuals (1112 [45%] male, mean age 55.6 years [SD 11.6], mean BMI 35.3 kg/m2 [SD 6.3], and 1385 [55%] with diabetes). All agents led to MASH resolution without worsening of fibrosis in a proportion of patients, with significant effects observed for tirzepatide and resmetirom. Tirzepatide (mean difference [MD] - 34.90% [95% CI: - 53.31 to - 16.49]) and resmetirom (MD - 31.45% [95% CI: - 35.93 to - 26.97]) significantly reduced hepatic steatosis as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF). Tirzepatide significantly reduced serum aminotransferase levels (ALT: MD - 30.90%, p < 0.00001; AST: MD - 20.71%, p < 0.00001). Although lanifibranor demonstrated improvements in lipid profiles (HDL-C + 9.87%, triglycerides - 26.90%), it did not achieve a statistically significant improvement in fibrosis (OR 1.26, p = 0.08). Gastrointestinal adverse events were frequently reported across all treatment arms. Tirzepatide and resmetirom significantly improved MASH resolution without worsening of fibrosis and reduced hepatic steatosis. All three agents lowered serum aminotransferase levels, while lanifibranor and resmetirom improved lipid profiles. Gastrointestinal adverse events were common, which may affect tolerability. Due to the limited number of trials for tirzepatide and lanifibranor, further large-scale studies are warranted to confirm their role in MASLD/MASH management.

The Role of GLP1 Receptor Agonists and Multi-agonist Incretin Therapies for Specific Obesity-related Health Conditions: Evidence and Rationale for Prioritisation.

Curr Obes Rep

Christo Albor, Oluwaseun Anyiam, Luke D Boyle +17 more

Study on chitosan/carrageenan core-shell nanoparticles for oral co-administration of insulin/exenatide enhance insulin secretion in type 2 diabetes.

Int J Biol Macromol

Tuong-Vy Nguyen, Ngoc-Hanh Cao-Luu, Thi-Bao-Tran Nguyen +2 more

This study developed and evaluated the feasibility of using core-shell chitosan and carrageenan nanoparticles for insulin and exenatide dual-delivery to control blood glucose levels in type 2 diabetes model. Core-shell nanoparticles were fabricated using the coaxial electrospraying technique, exploiting the electrostatic interactions between components to achieve controlled drug release in physicological media. Experimental results indicated that the prepared nanoparticles demonstrated proper physicochemical properties of an oral delivery system, including a hydrodynamic diameter around 300 nm, fitting well through the digestive wall and remaining somewhat stable in the physiologic milieu throughout time, and exhibited non-toxicity to multiple cell lines. The in vitro drug release approximately 80% from the nanoparticles was triggered by pH-sensitive behavior and controlled in spatiotemporal manners in simulated intestinal fluids with digestive enzymes, resulting in inhibition of premature release and self-sustained drug delivery. In type 2 diabetic mice, a single dose (100 IU kg-1) of nanoparticle generated a pronounced hypoglycemic response, achieving approximately a 45% reduction in blood glucose levels following 4 h oral administration and maintaining insulin plasma at a low level within 12 h owing to insulin and exenatide synergic stimulation effects. Remarkably, treatment with this nanoparticle significantly preserved pancreatic islets and averted type 2 diabetes complications within major organs such as the heart, liver, and kidneys, while maintaining an excellent systemic safety profile. This study evidenced that the nanoparticle-loaded insulin and exenatide were an encouraging long-acting formulation and validated a novel strategy to overcome multiple absorption barriers using polyelectrolyte complex nanoparticles from chitosan and carrageenan.

Bifunctional Peptide Amphiphile Hydrogel Orchestrates Concerted Antioxidant and Anti-Inflammatory Actions to Counter Myocardial Ischemia/Reperfusion Injury.

Adv Healthc Mater

Yuanyuan Wu, Siman Luo, Guanghui Xu +8 more

Myocardial ischaemia/reperfusion injury presents significant clinical challenges driven by a self-perpetuating cycle of oxidative stress and inflammation. Current therapeutic strategies fail to simultaneously address these interconnected pathological events. Here, we present T&A-Gel, a supramolecular peptide amphiphile hydrogel integrating α-tocopherol and Angiotensin-(1-7) (Ang-(1-7)) through covalent conjugation to enable localized co-delivery and synergistically disrupt this oxidative-inflammatory feed-forward circuit. Upon hierarchical self-assembly into filamentous nanofibres, T&A-Gel forms a sustained-release depot that exposes Ang-(1-7) moieties while sequestering hydrophobic α-tocopherol. This design enables α-tocopherol to scavenge excess reactive oxygen species, ameliorating oxidative mitochondrial dysfunction and reducing cardiomyocyte apoptosis, while exposed Ang-(1-7) acts as a selective Mas receptor (MasR) agonist, activating the protective MasR/PI3K/Akt signaling axis. This dual-action mechanism suppresses NF-κB nuclear translocation and inhibits pro-inflammatory cytokine cascades. In vitro, T&A-Gel significantly enhanced hypoxia/reoxygenation-injured cardiomyocyte viability. In vivo, T&A-Gel demonstrated prolonged retention with substantial reduction in infarct size and cardiac necrosis biomarkers. Quantitative analysis confirmed substantial attenuation of interstitial fibrosis and cardiomyocyte hypertrophy, translating into restored ejection fraction and reduced ventricular dilation with excellent biocompatibility. These findings establish injectable supramolecular hydrogels as a powerful strategy for disrupting the interconnected injury cascade via mechanistically complementary payloads, offering a paradigm for precision cardioprotection.

Cardiac biomarkers response under angiotensin receptor-neprilysin inhibitor: a sub-analysis of the NATRIUM-HF study.

ESC Heart Fail

Jolie Bruno, Aziz Daghmouri, Malha Sadoune +13 more

Natriuretic peptides (NPs) are central to the diagnostic and therapeutic management of heart failure (HF), yet their short-term dynamics under sacubitril/valsartan (S/V) therapy and during acute volume changes remain incompletely characterized. We aimed to assess changes in circulating biomarkers and response to standardized acute intravascular volume expansion and diuretic treatment before and after S/V initiation.

Prognostic value of cardiopulmonary exercise testing in connective tissue disease-associated pulmonary arterial hypertension at low and intermediate-low risk.

Clin Rheumatol

Yixin Zhang, Linwei Shan, Jiayi Dai +6 more

Pulmonary arterial hypertension (PAH) is a severe complication of connective tissue disease (CTD) and a leading cause of mortality in affected patients. Although the COMPERA 2.0 model is widely used for risk stratification in PAH, its ability to discriminate prognosis among low-risk patients remains limited. This study aimed to explore the prognostic predictive role of cardiopulmonary exercise testing (CPET) in CTD-PAH patients classified as low or intermediate-low risk by COMPERA 2.0.

The effect of centralized care on the management of postoperative fluctuations in plasma sodium concentration after pediatric suprasellar brain tumor surgery.

Pituitary

S C Hulsmann, D C Zaal, J P J van Gestel +9 more

Children undergoing neurosurgery for (supra)sellar tumors are at risk of developing arginine vasopressin-deficiency (AVP-D), which can cause severe sodium fluctuations and associated neurological complications, prolonged hospitalization and mortality. A previous Dutch study reported sodium shifts ≥ 10 mmol/L/24 h in 75.3% of patients with early postoperative AVP-D, with a maximum delta of 46 mmol/L/24 h. Since 2018, pediatric oncology care has been centralized in the Netherlands. We evaluated the impact of this centralization on postoperative sodium fluctuations in children with (supra)sellar tumors.

Current options for the treatment of anxiety in adults with autism spectrum disorder.

Expert Rev Neurother

Carmen Lopez-Arvizu, Jonathan Muniz

Anxiety affects approximately 30-40% of adults with autism spectrum disorder (ASD), yet its diagnosis and treatment remain underrepresented in the literature. Autism is a lifelong condition and addressing it across lifespan while considering its developmental stage is essential. Tailored clinical approaches are needed to accommodate communication, cognitive, and sensory differences.

Discordant Cortisol Responses to Spontaneous Hypoglycaemia Versus Adrenocorticotropic Hormone Stimulation: A Diagnostic Challenge for Hypothalamic-Pituitary-Adrenal Axis Assessment.

Indian J Endocrinol Metab

Pushpa Machineni, Asha Ranjan, Adlyne R Asirvatham +1 more

The hypothalamic-pituitary-adrenal (HPA) axis is a critical regulator of cortisol secretion, assessed via dynamic tests such as the insulin tolerance test and adrenocorticotropic hormone (ACTH) stimulation test. Discordant cortisol responses in recurrent hypoglycaemia that is, blunted secretion during hypoglycaemia but preserved under ACTH stimulation, pose a diagnostic challenge in evaluating adrenal insufficiency (AI).

Clinical characteristics, diagnosis, and treatment of Cushing's syndrome: analysis of a multicenter registry in Antioquia, Colombia.

Ther Adv Endocrinol Metab

Wilfredo Antonio Rivera-Martínez, María Johana Ramírez Castaño, Stefanía Cruz Calderón +9 more

Cushing's syndrome (CS) is a rare endocrine disorder caused by long-term exposure to excess cortisol and is linked to significant morbidity. Data from multiple centers in Latin America remains limited.

The role of agomelatine in appetite regulation and body weight in rats.

Exp Physiol

Engin Korkmaz, Yavuz Erden, Çiğdem Tekin +1 more

The hypothalamic nuclei play a central role in the synthesis of anorexigenic and orexigenic neuropeptides, which are regulated by peripheral hormones, like leptin and ghrelin. Melatonergic receptors (MT1/MT2) are prominently expressed in the arcuate nucleus of the hypothalamus - an essential hub for appetite control - and in peripheral metabolic tissues where leptin and ghrelin are secreted. Agomelatine, an antidepressant drug and potent MT1/MT2 agonist, offers potential for modulating appetite. This study aimed to investigate the impact of agomelatine on appetite regulation. Forty male Sprague-Dawley rats were randomly allocated into four groups, control (no treatment), vehicle control, agomelatine 20 mg/kg (Ago-20), and agomelatine 40 mg/kg (Ago-40), and administered oral gavage for 14 days. Body weight and food intake were recorded daily. At the end of the experiment, rats were euthanized and blood and hypothalamic tissue samples were obtained. Agomelatine significantly reduced body weight (Ago-40: 275.2 ± 7.2 g vs. control: 339.7 ± 8.3 g, P < 0.05) and food intake (Ago-40: 20.21 ± 1.32 g vs. control: 32.09 ± 1.58 g, P < 0.05) by day 14, without affecting water intake. Plasma ghrelin levels decreased (Ago-40: 22.54 ± 3.95 ng/dL vs. control: 46.67 ± 4.84 ng/dL, P < 0.05), while leptin increased (Ago-40: 552.30 ± 41.67 pg/mL vs. control: 271.10 ± 32.12 pg/mL P < 0.05). Hypothalamic orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) were suppressed (NPY, Ago40: 0.61 ± 0.02 vs. Control: 1.36 ± 0.1321; AgRP, Ago40: 0.52 ± 0.03 vs. Control: 1.49 ± 0.27, P < 0.05), while anorexigenic cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) were elevated (CART: Ago40: 1.19 ± 0.08 vs. Control: 0.92 ± 0.06; POMC: Ago40: 1.49 ± 0.17 vs. Control: 0.67 ± 0.10, P < 0.05). These findings suggest agomelatine promotes weight loss by modulating appetite-related hormones and hypothalamic neuropeptides, highlighting its potential as a therapeutic for obesity and metabolic disorders.

Effects of a sea level stay on pulmonary hemodynamics in patients with pulmonary arterial hypertension living in Quito near 2850m.

Chest

Silvia Ulrich, Julian Müller, Michael Furian +11 more

Amongst the >80 Mio people living >2500m are patients with pulmonary arterial hypertension (PAH).

The Role of TFEB-Regulated Autophagy in Intervertebral Disc Degeneration and Its Therapeutic Potential.

J Inflamm Res

Mengen Xue, Zhengfa Jiang, Zihao Wang +8 more

Intervertebral disc degeneration (IVDD) is a major cause of chronic low back pain, driven by nucleus pulposus cell (NPC) senescence, extracellular matrix imbalance, and chronic inflammation. Transcription Factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, has emerged as a pivotal player in degenerative diseases. By modulating autophagy-related genes, TFEB promotes the clearance of damaged components and maintains metabolic homeostasis in NPCs. Its dysfunction impairs autophagic flux, exacerbating cellular apoptosis, oxidative stress, and ECM degradation, thereby accelerating IVDD progression. Critically, this review is the first to systematically synthesize evidence positioning TFEB at the nexus of these pathological processes, establishing it as an integrative therapeutic target. We detail the molecular regulation of TFEB and its dysfunction in IVDD. Furthermore, we evaluate emerging TFEB-targeted strategies and discuss the key translational challenges. This work provides not only a mechanistic synthesis but also a forward-looking perspective on overcoming bottlenecks in TFEB-based therapy for IVDD.

A pathogenic Tau mutation drives autophagy-lysosome dysfunction that limits Tau degradation in a model of frontotemporal dementia.

Nat Commun

Farzaneh S Mirfakhar, Jacob A Marsh, Chihiro Sato +8 more

Tau accumulates in a group of neurodegenerative diseases known as tauopathies. A prevailing hypothesis has been that Tau degradation is impaired due to an age-related imbalance in the autophagy-lysosome pathway, but whether these defects are a cause or consequence of Tau accumulation remains unclear. Here we show that a disease-causing mutation in the MAPT gene, which encodes Tau, p.R406W, is sufficient to disrupt multiple steps of the autophagy-lysosome pathway in human neurons. Using Airyscan super-resolution imaging, we find that mutant Tau neurons accumulate Tau and phosphorylated Tau in dysfunctional lysosomes, exhibit reduced lysosome motility, impaired fusion of autophagosomes and lysosomes, and increased undegraded cellular cargo. Pharmacological enhancement of autophagy improves cargo clearance and lowers Tau levels, without restoring defects in lysosomal motility. Together, these findings demonstrate that mutant Tau directly perturbs cellular clearance pathways and suggest that boosting autophagy may help restore Tau homeostasis in tauopathies.

Oncocytic adrenocortical carcinomas: A clinicopathological and immunohistochemical review of 14 cases of a rare entity.

Indian J Pathol Microbiol

Niraj Kumari, Amit Agarwal, Navneet Tripathi +2 more

Oncocytic subtypes of adrenocortical carcinomas are rare tumor entities, with relatively better prognosis than the conventional subtype. Owing to its rarity, oncocytic adrenocortical carcinomas (OACCs) have not been studied extensively. The study aims to analyze the clinicopathological and therapy-relevant immunohistochemical profile of OACC.

Development of nanobody-conjugated LL37 for synergistic therapy against MDR Acinetobacter baumannii.

mSphere

Apisitt Thaiprayoon, Worrapoj Oonanant, Siriphan Boonsilp +10 more

Multidrug resistance (MDR) of the pathogen Acinetobacter baumannii is a major challenge to global healthcare due to the limited treatment options. The emergence of MDR bacteria necessitates innovative therapeutic approaches, especially given the associated economic burden and the rapid spread of infections. Conventional treatments such as antibiotics and vaccines face significant obstacles. Antimicrobial peptides (AMPs) such as LL37 have potential as an alternative treatment due to their broad-spectrum activity and ability to target specific bacterial structures such as the outer membrane protein A (OmpA). The efficacy of AMPs can be enhanced by using nanobodies (Nbs) that bind to bacterial OmpA, guiding LL37 precisely to its target. In this study, A. baumannii OmpA (AbOmpA)-specific Nbs (NbO7 and NbO13) were efficiently isolated through magnetic-activated cell sorting-based screening of a yeast surface display library, eliminating the need for specialized equipment. Nbs exhibited specific, dose-dependent binding to the target. Conjugation of Nbs with LL37 effectively inhibited the growth of MDR A. baumannii. This approach leverages the natural antimicrobial properties of AMPs and enhances their specificity and effectiveness by targeting bacterial cell surface proteins. LL37-conjugated AbOmpA-Nbs present a promising therapeutic strategy against MDR A. baumannii and other resistant pathogens.IMPORTANCEMultidrug-resistant (MDR) Acinetobacter baumannii poses a major global health threat due to its resistance to nearly all available antibiotics and its persistence in hospital settings. This challenge underscores the urgent need for new therapeutic approaches beyond conventional drugs. In this study, we developed an innovative strategy that combines the human antimicrobial peptide LL37 with nanobodies (Nbs) targeting the outer membrane protein A (OmpA), a key virulence and survival factor of A. baumannii. OmpA-specific Nbs were efficiently isolated from a fully synthetic library using a simple, low-cost selection approach without animal immunization. When conjugated with LL37, these Nbs bound specifically to OmpA and strongly inhibited MDR A. baumannii growth in vitro. Our findings introduce a simple yet powerful platform for generating targeted Nb-peptide conjugates, offering strong potential for adaptation against other antibiotic-resistant pathogens and contributing to the development of next-generation biologics to overcome antibiotic limitations.

Design and Screening of the Peptide SAMP-12aa Derived from LL-37, Which Exhibits Anti-H. Pylori Activity and Immunomodulatory Effects.

Molecules

Jianliang Lu, Qingyu Wang, Meisong Qin +3 more

The appearance of antibiotic-resistant strains of Helicobacter pylori (H. pylori) is leading to a decreased eradication rate of H. pylori infection. There is an urgent need to find new agents with antimicrobial mechanisms different from those of antibiotics, with therapeutic potential to clear colonization of H. pylori in the stomach. Some antimicrobial peptides (AMPs) possess bactericidal activity by enhancing the permeability of the outer membrane and damaging the integrity of the cell membrane. Bacteria are not susceptible to drug resistance through this antimicrobial mechanism. In this study, 28 short peptides containing 12 amino acid residues were designed based on nine amino acid fragments (KRIVQRIKD) from human cathelicidin LL-37, which is stable in gastric juice, and 3 amino acids were added at the C-terminus of the peptide. These designed peptides were not digested and degraded by pepsin at low pH values. The peptides were predicted using the online tool platform. Then, the strongest antimicrobial peptide, named SAMP-12aa (KRIVQRIKDVIR), was screened from 28 short peptides. Further studies found that SAMP-12aa retained anti-H. pylori activity after incubation in simulated gastric juice. The MIC and MBC of SAMP-12aa were 8 μg/mL and 32 μg/mL, respectively. SAMP-12aa showed good bactericidal kinetics. SAMP-12aa was found to have cell selectivity, penetrating and damaging bacterial cell membranes and exhibiting almost no toxicity to human cells at a relatively high concentration (128 μg/mL). Regulatory T (Treg) cells express CD25High with immunosuppressive activity that induces immune tolerance in response to H. pylori. Molecular docking prediction revealed that SAMP-12aa could target the active center of Foxp3. Flow cytometry analysis revealed that SAMP-12aa can inhibit Foxp3 activity and downregulate CD25 protein expression on CD4+ T cells, thereby reducing the development and differentiation of CD4+Foxp3+CD25High Treg cells with immunosuppressive effects. Further research revealed that the levels of the cytokine interferon-γ (IFN-γ), which activates CD8+ T-cell activity, were significantly elevated, and the levels of transforming growth factor-β (TGF-β), which inhibits CD8+ T-cell activity, were significantly reduced. The results of this study reveal that SAMP-12aa not only possesses antibacterial activity but also has immunomodulatory effects.

Fat, muscle, and anti-obesity medications in cardiovascular disease prevention.

Eur Heart J

Muhammad Shahzeb Khan, Muhammad Hamza Dawood, Yehuda Handelsman +4 more

The rapid expansion of anti-obesity treatments with glucagon-like peptide-1 receptor agonists has redefined weight management. A consistent component of this weight loss, however, involves not only fat mass but also lean body mass, including skeletal muscle. This raises concerns regarding sarcopenia, frailty, and metabolic resilience that may attenuate long-term cardiovascular risk reduction. Muscle loss with these drugs is multifactorial, related to caloric restriction, anabolic resistance, and hormonal shifts. Emerging agents targeting the myostatin/activin pathway, ligand traps, and selective androgen receptor modulators may increase muscle quality and have synergistic benefit with incretin-based therapies. Resistance training is currently the suggested strategy for preserving skeletal muscle and functional capacity during pharmacologic weight loss, while adjunctive strategies such as optimized protein intake and nutraceuticals may further mitigate muscle catabolism. A paradigm shift is needed in obesity treatment away from total weight loss towards high-quality weight loss that preserves or enhances muscle mass, optimizing body composition and supporting durable cardiovascular risk reduction. Future research should study lean mass preservation as a treatment goal, redefine trial endpoints, and validate emerging combination interventions for optimal body composition. This manuscript reviews the evidence on muscle loss with pharmacologic weight loss therapies, its mechanistic underpinnings, explores emerging agents designed to preserve lean tissue, and outlines strategies to optimize body composition in the context of cardiovascular prevention.

The Role of Glucagon-Like Peptide-1 Receptor Agonists in Prompting a Meaningful Improvement in Alcohol Use Disorder.

J Prim Care Community Health

Alyx Meilinger, Michael A Campbell, Hannah M Reynolds +1 more

Emerging research suggests a potential role for glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in alcohol use disorder (AUD), because GLP-1 receptors are present in the brain regions involved in dopamine signaling and the human reward system. We present the case of a man prescribed GLP-1 RAs for obesity who had concomitant AUD. A 34-year-old man was referred to a family medicine clinic for medication therapy management of obesity. His medical history was notable for bipolar disorder, class 2 obesity, and obstructive sleep apnea (OSA). His Alcohol Use Disorders Identification Test score indicated high-risk alcohol use. Over the course of 10 months using an injectable GLP-1 RA (semaglutide), the patient showed a clinically significant decrease in both body weight and alcohol consumption. Although this patient initially sought care for weight loss goals to improve quality of life and symptoms of OSA, after 10 months of treatment with semaglutide he reported a considerable decrease in alcohol consumption leading to mental, social, and home life improvements. Our aim in presenting this case is to illustrate the potential benefit of GLP-1 RAs for decreasing alcohol consumption levels in a patient with multiple comorbid conditions. The case adds to the growing body of evidence supporting the exploration of GLP-1 RAs for the treatment of AUD. Additionally, it underscores the need to enhance AUD screening efforts within family medicine clinics to identify high-risk persons and provide timely interventions.

Cardiorenal Outcomes With Tirzepatide Compared With Dulaglutide in Patients With Diabetes and Cardiovascular Disease: A Post Hoc Analysis of the SURPASS-CVOT Randomized Clinical Trial.

JAMA Cardiol

Steven E Nissen, Kathy Wolski, David D'Alessio +6 more

The dual glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide was noninferior to a GLP-1 agonist, dulaglutide, for effects on the composite outcome of cardiovascular death, myocardial infarction (MI), or stroke. However, comparison for a comprehensive range of major adverse cardiovascular and kidney outcomes has not been reported.